Vasodilators are used in coronary artery disease to increase blood flow to damaged or ischemic tissue; they are similarly used for treating strokes often resulting in major improvements in a patient. However, undesirable side effects present a drawback to vasodilators currently in use. For example, sodium nitroprusside causes thiocyanate intoxication, methemoglobinemia, acidosis and cyanide poisoning according to Vidt, D. G. In: Goodfriend T.L. et al., Eds., Hypertensive primer, 2nd Ed., (1999) pp. 437-442. Additionally, sodium nitroprusside is extremely light sensitive such that the intravenous (IV) delivery sets carrying it must be light resistant. Glyceryl trinitrate has side effects which include vomiting, flushing, headache and methemoglobinemia. Use of this compound requires a special delivery system to prevent binding of the drug to the infusion line. Many of the currently available drugs including sodium nitroprusside, glyceryl trinitrate, diazoxide, fenoldopam, hydralazine, nicardipine and phentolamine cause marked tachycardia due to reflex activation of the sympathetic nervous system as described by Vidt, D. G. supra. Tachycardia increases myocardial oxygen demand and thus may worsen myocardial ischemia. Other rapidly acting vasodilators such as verapamil, labetalol and esmolol slow cardiac conduction and may cause heart block.
Many currently-employed drugs such as nicardipine, verapamil, diazoxide, hydralazine and labetalol display slow offset of action which makes the dose titration difficult. Even fenoldopam and esmolol have an offset of action of 15 to 30 minutes. None of the currently available rapid-onset/-offset vasodilators preferentially protects blood flow to all of the vital organs (brain, heart, kidneys and gut); nor do the currently available vasodilators have the beneficial ancillary actions that could reduce the risk of cardiovascular events.
Thus, there is a need for drugs which act specifically as vasodilators, lack the undesirable characteristics of prolonged half-life with the induction of tachycardia and protect blood flow to vital organs. Activators of adenosine A2A receptors have potential as vasodilators which lack many of these undesirable side-effects.
Adenosine is an important neuromodulator in the central and peripheral nervous systems of mammals. As a neuromodulator, adenosine alters the rate at which a nerve cell fires. Peripherally, adenosine is likely to be either constitutively released, or released at times of high or low metabolic activity. Importantly, neuromodulators such as adenosine may act pre- or post-synaptically and may be subsequently taken up or metabolized.
The physiological effects of adenosine were first noted by Drury and Szent-Gyorgyi in J. Physiol. 68: 213-237 (1929). This study reported that extracts from various tissues including heart muscle, brain, kidney and spleen had profound effects on cardiovascular parameters. Further investigation revealed that the active substance in the tissue extracts was adenosine. Following this finding, investigation of the effects of adenosine on the cardiovascular system continued for the next 20 years. Beginning in the 1950's and continuing into the early 1960's, Berne and colleagues investigated the effects of adenosine on coronary blood flow as described in Jacob, M. I. and Berne, R. M. Amer. J. Physiol 198:322 (1960). This work led to the hypothesis that cardiac adenosine production plays an important role in the metabolic regulation of coronary blood flow, an hypothesis that has been expanded to include other organs including the brain and kidneys.
Currently, there are at least four known subtypes of adenosine receptors including the A1, A2A, A2B and A3 receptors which have been cloned from animal or human sources. Adenosine receptors are members of the G-protein coupled receptor (GPCR) superfamily and mediate the stimulation or inhibition of adenylyl cyclase activity, and hence cyclic adenosine monophosphate levels. Adenosine receptors are currently the smallest cloned members of the GPCR superfamily.
Adenosine receptors are involved in a vast number of peripheral and central regulatory mechanisms including vasodilation, cardiac depression, inhibition of lipolysis, inhibition of insulin release and potentiation of glucagon release in the pancreas, inhibition of vascular smooth muscle cell growth, stimulation of endothelial cell growth, angiogenesis, wound healing and inhibition of neurotransmitter release from nerve terminals. A well-known class of adenosine receptor antagonists encompasses xanthines that include caffeine and theophylline which are commonly found in tea, coffee and cocoa. Adenosine itself has been used in the treatment of supraventricular tachycardia and may also be utilized as a diagnostic tool in the study of cardiac abnormalities.
Subsequent to the characterization of these adenosine receptors, research has focused on developing pharmacotherapeutic agents that are selective for one of the adenosine receptor subtypes. Consequently, a large array of highly selective drugs for adenosine A1 and A2A receptors has been synthesized as described by Jacobson, K. A. et al. in J. Medicinal Chem. 35:407-422 (1992).
A number of selective analogues of adenosine receptor antagonists and agonists have been developed through a designer approach referred to as “functionalized congener” synthesis as described in U.S. Pat. No. 4,968,672 to Jacobson, as well as in Jacobson et al., Mol. Pharm. 29: 126-133 (1985), both of which are incorporated herein by reference in their entirety for methods and background relating to functionalized congener synthesis. Utilizing this method, analogues of adenosine receptor ligands bearing functionalized chains have been synthesized and attached covalently to various organic moieties such as amines and peptides. Attachment of polar groups to xanthine congeners has been found to increase water solubility.
Presently, the majority of A1 and A2A receptor agonists are derivatives of adenosine. For example, numerous modifications of the N6-position on adenosine with hydrophobic functionalities have yielded highly selective A1 receptor agonists such as N6-cyclopentyladenosine, N6-cyclohexyladenosine, and N6-phenylisopropyladenosine. Generally, N6-substituted adenosine derivatives are selective for the A1 receptor; however, some N6-substituted adenosine analogs are highly potent A2A receptor agonists, e.g., N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl] as described by Bridges, A J. et al. J. Medicinal Chem. 31: 1282-1285 (1988). Although modifications to the purine ring usually lead to lower activity, an exception is 1-deazaadenosine which retains high affinity for adenosine receptors. The 2-position of adenosine has also been modified in order to produce selective adenosine receptor agonists. CV 1808, a 2-arylamino adenosine analog described by Jarvis, M. F. et al. J. Pharmacol. Exp. Ther. 251:888-893 (1989) has modest affinity and selectively for A2A receptors. Additional 2-position modifications led to the generation of 2-alkoxyadenosines and 2-alkynyladenosines, some of which are potent A2A receptor agonists.
Selected ribose modifications have also generated potent A2A receptor agonists. For example, placement of an amide in the 5′-position of the ribose created adenosine-5′-N-ethyluronamide, which has greater potency at A2A receptors compared with adenosine, yet still retains A2A receptor agonist activity. Further modification on the 2-position of adenosine-5′-N-ethyluronamide led to the discovery of 2-[4-[(2-carboxyethyl)phenyl]ethylamino]-5′-N-ethylcarboxamidoadenosine, also known as CGS 21680 as described by Jarvis et al., supra. CGS 21680 is not only 140-fold more selective for the A2A versus the A1 receptor, but also exhibits a high affinity for A2A receptors while exhibiting no affinity for A2B receptors. Although thio-substitution for the 4′-oxygen in 2-chloroadenosine enhanced affinity for A2A receptors, other ribose modifications have resulted in decreased activity at adenosine receptors. In particular, substitutions at 2′-and 3′ positions appear to nearly always reduce activity.